Myeloproliferative neoplasms (MPNs) are frequently associated with a mutation in the non-receptor tyrosine kinase JAK2 at codon 617 that changes valine (V) to phenylalanine (F). This activating JAK2V617F mutation is not only found in the majority of patients with myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis, but can also be present at lower frequency in other myeloid malignancies, including acute myeloid leukemia and myelodysplastic syndromes. JAK2V617F is thought to be instrumental for the overproduction of myeloid lineage cells and in mice—it is sufficient by itself to cause a myeloproliferative disease. Even though the crystal structure of the JAK2 kinase domain has been solved, it is not known how exactly the V617F mutation in the pseudokinase domain leads to constitutive activation. The JAK2V617F mutation seems insufficient for its kinase activation and association with a cytokine receptor, such as the erythropoietin receptor (EpoR), appears to be required. Lack of a functional FERM domain in JAK2V617F, which mediates interaction with cytokine receptors, results in a loss of its transforming activity. It is likely that inhibitory constraints, normally overcome by ligand binding, are targeted by the JAK2V617F mutation, therefore leading to hyperresponsiveness or factor-independent growth.
Most, if not all, tyrosine kinase inhibitors that are currently used to target transforming tyrosine kinase oncogenes in various cancers are susceptible to resistance, as a result of point mutations in the corresponding kinase domain. Thus, a need exists to identify mutations in the JAK2 JH1 domain that would confer resistance and compare the sensitivity of different JAK inhibitors that are currently in clinical trials towards these mutations.